Blindness, caused by destruction of retinal cells, such as that occurring in diabetes retinopathy and retinitis pigmentosa, is a serious health problem. Functional and structural impairment of the retina which is a common consequence of infection, inflammation, degeneration, aging or trauma, is at present virtually non-treatable. The ultimate goal of our study is to be able to implant functional retinal cells into the posterior compartments of blinded eyes as a means of restoring vision. Since therapeutic retinal transplantation of the type we envision will undoubtedly make use of histoincompatible tissue, the immediate goals of our studies are to: 1) describe the unique features of immune responses evoked by intraocular grafts of allogeneic and syngeneic retinal tissue, 2) understand the immune mechanisms of rejection of intraocular retinal grafts, and 3) explore experimental approaches to prevent immune rejection of intraocular retinal grafts. The studies described in this application are based on our recent preliminary results and are designed to test the hypothesis that survival of healthy intraocular retinal grafts is dictated by graft immunogenicity and the host intraocular microenvironment. We intend to answer the following questions: 1) Do allogeneic retinal tissues, which are placed in the anterior chamber, vitreous cavity and subretinal space of the eye, express alloantigens that can induce systemic immune responses that prejudice long-term engraftment? 2) Are autoantigens expressed on retinal grafts immunogenic and can they offer a significant immunologic barrier to intraocular retinal graft survival? 3) Can the induction of deviant immunity directed at alloantigens and autoantigens on intraocular retinal transplants mitigate graft rejection and promote survival? and 4) Are microenvironmental factors produced by retinal grafts and host intraocular tissues important determinants of successful intraocular engraftment? The techniques used in our studies will consist of clinical, histopathological and immunological approaches. The results are expected to explore the nature of immune privilege evoked by intraocular retinal grafts, and therefore allow us to develop immunological strategies that can be used to promote survival of intraocular retinal grafts. This will lead our research toward our ultimate goal of therapeutical retinal transplantation. In addition, since the nature of these studies is to focus on potential interactions between cells and molecules of the neural system and their counterparts in the immune system, it is possible that the principles deduced therefrom will shed light on the pathogenesis of idiopathic, destructive retinal disease. Accordingly, this information should prove useful in designing further strategies to enhance or inhibit communications between the eye and the immune system as a means of promoting and ensuring the preservation of vision.